Phenotypic and genotypic diversity in Neisseria gonorrhoeae: Using population biology to understand antimicrobial resistance and pathogenesis

淋病奈瑟菌的表型和基因型多样性：利用群体生物学了解抗菌素耐药性和发病机制

• 批准号: 2117464
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2117464
• 关键词: Phenotypic; genotypic; diversity; Neisseria; gonorrhoeae

The global spread of antibiotic resistance is a significant and increasing threat to global human health.Amongst increasing threats is the sexually transmitted disease gonorrhoea, for which last resorttreatment failures (i.e. third generation cephalosporins) have been reported in numerous countries.The WHO has highlighted that gonorrhoea may soon become untreatable as no vaccine or new drugsare currently available. The population structure of the causative pathogen Neisseria gonorrhoeae iscomplex and non-clonal due to the high level of genetic recombination that occurs between isolates.Prolific genetic recombination can confound population studies on gonococci, especially as suchstudies often focus on limited gene numbers such as Multi-locus sequence typing (MLST). Geneticplasticity allows gonococci to quickly generate a range of phenotypes though gene phasing andrecombination, the fittest of which can be selected for in vivo, facilitating rapid adaptation within thedifferent mucosal niches infected by these bacteria. This PhD aims to profile the antibiotic resistanceof gonococcal isolates from distinct mucosal sites and study the genomic and virulence relatedphenotype of these isolates. Linkage of these traits to the dynamics of infection transmission will beexamined through mathematical modelling. The successful candidate will determine the presence ofkey virulence factors by distinct immunoassays and proteomic, and infect cell lines representative ofthe male and female mucosal surfaces mimicking in vivo culture conditions with a diverse range ofclinical isolates of Ng. Minimal inhibitory concentrations (MICs) for clinically relevant antibiotics willbe assayed. For each isolate selection the genome will be sequenced plus any associated plasmididentified. Finally, data for MIC, virulence factor presence genomic diversity and cell line infectivitywill inform mathematical models to investigate potential evolutionary mechanisms of action.The outcomes are of translational importance: we will improve understanding of in vivo selection inrelation to antimicrobial susceptibility and virulence. In addition, we will identify if niche specificity isan important consideration for bacterial phenotypes that may then be utilised in using antimicrobials.Overall this project will provide multi-discipline training and improve our understanding of gonococcalpopulation biology.

抗生素耐药性的全球传播是对全球人类健康的一个重大且日益严重的威胁。在日益严重的威胁中，性传播疾病淋病是最后一种治疗方法（即第三代头孢菌素）在许多国家都有报道失败。世界卫生组织强调，淋病可能很快变得无法治疗，因为目前没有疫苗或新药。淋病奈瑟菌是淋球菌的主要致病菌，其种群结构复杂，且具有非克隆性，大量的基因重组会干扰淋球菌的种群研究，特别是当淋球菌的种群研究往往集中在有限的基因数量上时，如多位点序列分型（MLST）。遗传可塑性允许淋球菌通过基因定相和重组快速产生一系列表型，其中最合适的可以在体内选择，促进在这些细菌感染的不同粘膜生态位内的快速适应。本博士学位的目的是描述不同粘膜部位淋球菌分离株的抗生素耐药性，并研究这些分离株的基因组和毒力相关表型。将通过数学模型来研究这些特征与感染传播动力学之间的联系。成功的候选者将通过不同的免疫测定和蛋白质组学确定关键毒力因子的存在，并感染代表男性和女性粘膜表面的细胞系，模拟体内培养条件，使用多种临床分离的Ng。将测定临床相关抗生素的最小抑菌浓度（MIC）。对于每个分离株选择，将对基因组进行测序，并鉴定任何相关的质粒。最后，MIC、毒力因子存在的基因组多样性和细胞系感染性的数据将为研究潜在的进化作用机制的数学模型提供信息，这些结果具有翻译的重要性：我们将提高对与抗菌药物敏感性和毒力相关的体内选择的理解。此外，我们将确定是否小生境特异性是细菌表型的重要考虑因素，然后可以在使用antimicrobiages.Overall这个项目将提供多学科的培训，提高我们对淋球菌种群生物学的理解。